J Med Biochem 2010; 29 (4)
DOI: 10.2478/v10011-010-0037-4
UDK 577.1 : 61
ISSN 1452-8258
J Med Biochem 29: 231–236, 2010
Review article
Pregledni ~lanak
DIAGNOSIS OF THYROID DISEASE: PRINCIPLES AND PROBLEMS
DIJAGNOSTIKA TIROIDNE BOLESTI: PRINCIPI I PROBLEMI
Milo{ @arkovi}
School of Medicine, University of Belgrade, Belgrade, Serbia
Clinic of Endocrinology, Clinical Center of Serbia, Belgrade, Serbia
Summary: Conceptually, thyroid disorders can be classified
into four groups, namely: 1. disorders of thyroid morphology,
2. disorders of thyroid function, 3. presence of thyroid autoimmunity, and 4. diagnosis and follow-up of thyroid
carcinoma. Of course, these groups are non-exclusive, and
often there is overlap between the groups. Ultrasound exam
is a standard for the diagnosis of the disorders of thyroid
morphology. To diagnose disorders of thyroid function TSH
and thyroid hormones should be measured. Presence of
thyroid autoimmunity is confirmed by measuring antibodies
against thyroid-specific antigens. Thyroid peroxidase (TPO),
thyroglobulin (Tg) and TSH receptors antibodies are used in
the diagnosis, follow-up and prognosis of autoimmune
thyroid disorders. The measurement of serum thyroglobulin
has no role in the diagnosis of thyroid cancer, but it is used in
the follow-up of patients treated for differentiated thyroid
carcinoma of the follicular epithelium. Medullary thyroid
cancer (MTC) produces calcitonin and carcinoembryonic
antigen (CEA), but calcitonin is specific for MTC. In subjects
with MTC, genetic testing should be done, and in positive
cases family screening is necessary.
Keywords: autoantibodies, calcitonin, thyroglobulin,
thyroid diseases, thyroid function tests, thyroid hormones
Introduction
Conceptually, thyroid disorders can be classified
into four groups. These groups are: 1. Disorders of
the thyroid morphology, 2. Disorders of the thyroid
function, 3. Presence of thyroid autoimmunity and 4.
Diagnosis and follow-up of thyroid carcinoma. Of
Address for correspondence:
Milo{ @arkovi}
Clinic of Endocrinology
Dr Suboti}a 13, 11000 Belgrade
PAK 112113, Serbia
Fax: +381-11-3639-776
e-mail: mzarkovªeunet.rs
Kratak sadr`aj: Konceptualno, poreme}aji {titaste `lezde
se mogu svrstati u ~etiri grupe: 1. poreme}aji morfologije
{titaste `lezde, 2. poreme}aji tiroidne funkcije, 3. prisustvo
tiroidne autoimunosti i 4. dijagnoza i pra}enje karcinoma
{titaste `lezde. Naravno, ove grupe se ~esto preklapaju. Za
dijagnostiku poreme}aja morfologije {titaste `lezde najbitniji
je ultrazvu~ni pregled. Za dijagnozu poreme}aja tiroidne
funkcije neophodno je odre|ivanje TSH i tiroidnih hormona.
Prisustvo tiroidne autoimunosti potvr|uje se merenjem antitela na tiroidno specifi~ne antigene. Za dijagnozu, pra}enje i
prognozu autoimunih bolesti {titaste `lezde koriste se antitela
na tiroidnu peroksidazu (TPO), tireoglobulin (TG) i antitela na
TSH receptore. Odre|ivanje tireoglobulina u serumu nema
zna~aj u dijagnostici karcinoma {titne `lezde, ali se koristi u
pra}enju bolesnika le~enih od diferentovanog karcinoma tiroide. Medularni tiroidni karcinom (MTK) sekretuje kalcitonin
i karcinoembrioni antigen (CEA), ali je kalcitonin specifi~an za
MTK. Kod obolelih od MTK neophodno je genetsko testiranje
a u pozitivnim slu~ajevima potrebno je i gensko testiranje
srodnika.
Klju~ne re~i: autoantitela, kalcitonin, tireoglobulin, tiroidna bolest, testovi tiroidne funkcije, hormoni {titaste `lezde
course, these groups are non-exclusive, and often
there is overlap between the groups.
Disorders of thyroid morphology
Among the most common disorders in the
human pathology are disorders of the thyroid morphology. The thyroid could be enlarged, presenting as
goiter, or nodules could be present. A thyroid nodule
is any focal lesion different from the normal gland,
and can be a cyst, carcinoma, lobule of normal tissue
or adenoma (1). Using palpation as the sole
diagnostic method, the established thyroid nodule
prevalence is 3% in the whole population, 6.4% in
232 @arkovi}: Diagnosis of thyroid disease
females and 1.5% in males (2, 3). However, using the
ultrasound thyroid nodules can be detected in about
60% of the population, what correlates well with the
autopsy data of 50% prevalence (4, 5). About 5% of
all thyroid nodules, regardless of the size, are
malignant (6). Ultrasound can also be used in the
diagnosis of different types of thyroiditis (7). Therefore, ultrasound exam is a standard for the diagnosis
of disorders of the thyroid morphology. Thyroid scintigraphy is less used today, but it gives a functional
morphology of the thyroid.
Disorders of thyroid function
Although disorders of the thyroid morphology
are among the most common conditions in the
human pathology, disorders of the thyroid function
are among the most frequent reasons for the
endocrine testing. Thyroid function is evaluated by
measuring TSH and thyroid hormones.
Disorders of the thyroid function can be caused
by diseases of the thyroid gland (primary thyroid
disease) or diseases of the pituitary or hypothalamus
(secondary thyroid disease). In addition, there are
disorders caused by the TSH receptor mutations or by
the resistance to thyroid hormone. Differential
diagnosis of primary and secondary thyroid dysfunction depends on measuring both TSH and thyroid
hormones, so they should both be measured at least
once in every patient.
When a thyroid function disorder is caused by a
primary thyroid disease, the TSH is a cornerstone of
diagnosis. In the same patients, TSH is the single most
important analyte in the assessment of the treatment
effect. There are multiple reasons for this. First, TSH is
a major regulator of the morphologic and functional
states of the thyroid. Secondly, TSH is a measure of
thyroid hormone influence on the brain and pituitary.
Thirdly, there is a log linear relationship between
thyroxine and TSH, meaning that small changes in
thyroxine will cause large changes in TSH (8). Recent
data suggest that the relationship between TSH and
thyroxine might be even more complex (9). However, it
takes 6–12 weeks for pituitary TSH secretion to reequilibrate to the new thyroid hormone status, when
the thyroid status is changed (10). Therefore, TSH is
good for long-term monitoring, especially of hypothyroid patients, as it does not depend on the relation
of TSH sampling and time of thyroxine treatment.
However, during periods of unstable thyroid status,
such as occurs in the early phase of treating hyper- or
hypothyroidism or changing the thyroxine dose, the
TSH concentration can be diagnostically misleading
(10). TSH isoforms with different biologic activity can
also be a diagnostic problem (11). In addition, inter ference from heterophilic antibodies can produce unexpected results (12). Nevertheless, recent research
showed that majority of TSH assays have excellent
quality of performance (13).
Some drugs cause TSH suppression. Most often
used are glucocorticoids, dopamine agonists and
somatostatin analogs. Metformin has also been
reported to cause TSH suppression (14).
During the last few years, establishing the upper
limit of the TSH reference range has been the subject
of numerous discussions and considerable research
(15–17). The key question is whether the upper limit
should be reduced from about 4 mIU/L to 3 or 2.5
mIU/L, and if there is a need for race, age and
gender specific reference ranges (17–19). These
discussions are caused by the specific distribution of
TSH values. In a reference population (one considered to be without thyroid disease), the TSH distribution is rightskewed. However, the reason for the
right skew of the TSH distribution is a matter of
controversy. Some authors suggest that occult thyroid
dysfunction is the cause of increased TSH values,
while others suppose that a mixture of several normal
distributions, due to sex, age, genetics, causes the
right-skewed distribution (16, 20). Therefore, interpretation of the TSH reference range will depend on
the conceptual framework explaining reasons for the
TSH distribution. Another confounding factor is the
method used to measure TSH. The use of older
analytical methods to measure TSH resulted in a
lower upper limit of the TSH reference range as compared to contemporary ones (21, 22).
Another problem, related to the upper reference
range of TSH, is a question of mild (subclinical) hypothyroidism. Subclinical (mild) hypothyroidism is
defined as an increased serum TSH in the presence
of a normal serum FT4 concentration. Please note
that increased and normal refer to values above or
within the population-based reference ranges of these
hormones (23). Clinical symptoms are usually very
vague or even absent, and are often not specific to
hypothyroidism. However, we still do not have
adequate studies to assess the benefit of treatment of
these patients. Most experts are inclined to treat
patients with subclinical hypothyroidism. However, all
agree that fertile women with subclinical hypothyroidism must be treated, even before conception, and
that they should be treated and carefully monitored
throughout pregnancy (24).
For a long time total thyroid hormone measurements (TT4 and TT3) have been the cornerstone of
thyroid dysfunction diagnosis. It should be noted that
biological markers of tissue hypothyroidism (ankle
reflex time, clinical severity score, total cholesterol
and creatinine kinase) do not correlate with TSH, but
have very good correlation with the free T4 (FT4) and
free T3 (FT3) concentration (25). Interestingly, psychological well-being, measured using General
Health Questionnaire-12 and Thyroid Symptom
Questionnaire correlated well with the TSH and FT4
concentration, but not with the FT3 concentration
(26).
J Med Biochem 2010; 29 (4)
Thyroxine in the circulation is approximately
99.97% bound to the plasma proteins (TBG 60–75%,
TTR/TBPA 15–30%, albumin about 10%). In the circulation, 99.7% of triiodothyronine is protein-bound,
primarily to TBG (12, 14). During the previous fifty
years, different technologies were used to measure total
thyroxine (TT4) in the circulation. However, despite
changes in the methodology it has remained a
remarkably robust determination, with minimal changes
in reference values (11). Total hormone measurement
should be proportional to that of free hormone in
patients with similar binding protein concentrations.
Unfortunately, many conditions in clinical practice are
associated with binding protein changes. Additionally,
some patients have abnormal thyroid hormone binding
proteins such as thyroid alterations, so that total
hormone measurement becomes unreliable. Therefore,
free hormone measurements are more commonly
used. Regrettably, separating the free hormone from
the protein-bound is technically very demanding
(equilibrium dialysis and ultrafiltration), and available
only in reference laboratories (27, 28). In routine
clinical practice FT4 and FT3 are not directly measured,
but estimated using different methods. It should be
noted that all current FT4 and FT3 estimate tests are to
some extent binding-protein dependent. In fact, a
recent study has shown that FT4 immunoassays
correlate better with total than free T4 concentrations,
although this conclusion has been disputed (29–32).
Due to these considerations, there is a renewed interest
in using TT4 measurements instead of FT4 estimates in
pregnancy. Reference range is adjusted by a factor of
1.5 to compensate for the pregnancy induced TBG
elevation (33–35).
Presence of thyroid autoimmunity
Tests for antibodies against thyroid-specific antigens, thyroid peroxidase (TPO), thyroglobulin (Tg)
and TSH receptors are used in the diagnosis, followup and prognosis of autoimmune thyroid disorders.
TPO Ab is considered a marker of Hashimoto
thyroiditis. Presence of TPOAb significantly increases
the risk of developing hypothyroidism (Odds ratio of
6.1), while an isolated increase in TgAb does not
confirm the risk of hypothyroidism (odds ratio of 0.6).
If both TPOAb and TgAb are present, the risk of
developing hypothyroidism is very high (Odds ratio of
34.7) (36). Whickham survey also showed the importance of TPOAb as a risk factor for the development
of hypothyroidism. Interestingly, there was a sexual
dimorphism, with males having higher risk compared
to females. Odds ratio of developing hypothyroidism
when TPOAb were present in females with normal
TSH was eight. If both TPOAb and TSH were
increased the odds ratio was 38 in females and 178
in males (37). TPOAb prevalence is about 10% in
males older than 20 years. In adult females, TPOAb
prevalence rises with age. The lowest prevalence is
233
found in the age group from 20 to 29 years (12.6%)
and the highest in persons over 80 (31.4%) (36).
However, serial measurements of the TPOAb
concentration are not recommended. This is because
the treatment addresses thyroid dysfunction and not
the thyroid autoimmunity. On the other hand, it is
important to determine TPOAb as a risk factor for
developing thyroid dysfunction in patients receiving
Amiodarone, Interferon-alpha, Interleukin-2 or Lithium
therapies (11).
During pregnancy, the presence of TPOAb has
been linked to reproductive complications such as
miscarriage, infertility, IVF failure, fetal death, pre-eclampsia, pre-term delivery and post-partum
thyroiditis and depression. However, it seems that the
main cause of these complications is a mild hypothyroidism, and that thyroxine supplementation prevents
complications (38). Recently, it was found that both
subclinical hypothyroidism and the autoimmune
thyroid disorder are independently associated with
very early pregnancy loss (39). Therefore, determination of TPOAb should be considered in pregnant
females, or in females planning pregnancy. However,
there is still no formal recommendation with regard to
this.
TgAb measurement is primarily used as an
adjunctive test to the serum Tg measurement when
monitoring patients with differentiated thyroid
cancers (DTC). Current guidelines recommend that
TgAb should be measured by a sensitive immunoassay method, prior to serum Tg determination (10,
40). Measurement of TgAb in patients with autoimmune thyroid disease is less useful (36).
The major antigen of Graves’ disease is the TSH
receptor. In Graves’ disease TSH receptor antibodies
(TRAb) bind to the TSH receptor, induce thyroid
growth and cause an increased rate of thyroid
hormone production and secretion. These antibodies
are referred to as thyroid-stimulating antibodies. However, a receptor antibody can act as a TSH antagonist
(thyroid-inhibiting or blocking antibodies). TRAbs are
not detectable in the normal population by the use of
currently available methods (41). To define whether
the TRABs are stimulating or inhibitory, bioassay must
be used. However, in clinical settings receptor-based
assays are used. Receptor-based assays cannot
differentiate between stimulating and inhibiting
TRAbs, so the measured antibodies are sometimes
referred to as thyroid-binding inhibitory immunoglobulins (TBII). Serial measurements of the TRAb
concentration are useful, as it correlates with
prognosis in Graves’ disease. A TRAb concentration
less than 1.5 IU/L after 12 months of treatment implies
good prognosis, while a TRAb concentration over 5.1
IU/L after 12 months or 2.8 IU/L after 24 months of
treatment indicates a severe course of disease (42).
234 @arkovi}: Diagnosis of thyroid disease
Diagnosis and follow-up
of thyroid carcinoma
The diagnosis of differentiated thyroid carcinoma of the follicular epithelium is based on the
clinical exam, ultrasound and fine needle aspiration
biopsy (FNAB) (43, 44). The measurement of serum
thyroglobulin has no role in the diagnosis of thyroid
cancer (40, 43, 45, 46). In subjects with the thyroid
gland, thyroglobulin concentration correlates with the
size, and not with the nature of thyroid pathology
(47). Thyroglobulin concentration is also dependent
on iodine intake (48). In patients treated for differentiated thyroid carcinoma by total thyroidectomy
and ablative dose of radioactive iodine, thyroglobulin
is a marker of tumor presence. Measuring thyroglobulin preoperatively has been suggested, as it
provides information regarding the tumor’s intrinsic
ability to secrete Tg. This obviously influences the
utility of using serial serum Tg measurements to serve
as a tumor marker to detect cancer recurrence postoperatively (11). Blood for the thyroglobulin determination should be sampled either before or more
than two weeks after FNAB (10). During the followup thyroglobulin should be determined after TSH stimulation using recombinant TSH or thyroxine withdrawal (43). The measurement of thyroid-specific
mRNA in the blood may provide better markers in the
future.
Medullary thyroid cancer (MTC) presents as part
of an inherited disorder in about 20–25% of cases
and in others as a sporadic tumor. MTC produces
calcitonin and carcinoembryonic antigen (CEA), but
calcitonin is specific for MTC. Tumor dedifferentiation
is associated with a fall of CT and increasing CEA,
and this is a bad sign (49). Diagnosis is based on the
calcitonin measurement, and calcitonin measurement is recommended in all subjects with thyroid
nodules (43). In subjects with MTC genetic testing
should be done, and in positive cases family
screening is necessary (50).
For the diagnosis of a thyroid disorder and the
patient follow-up, it is essential to correlate the clinical findings, visualization data and laboratory
results. Therefore, close collaboration between
different medical profiles is necessary for the proper
care of thyroid patients.
Conflict of interest statement
The author stated that there are no conflicts of
interest regarding the publication of this article.
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Received: July 4, 2010
Accepted: July 15, 2010